Msac application 1173

Delivery of the intervention

The applicant proposes that NSCLC patients would require one EGFR gene mutation test in their lifetime. This test would be performed immediately following pathological diagnosis of NSCLC and irrespective of the stage of disease, utilising the same biopsy material used for this diagnosis (base case). Alternatively, this could be performed by retrieving and retesting the biopsy sample when the patient’s disease status reaches Stage IIIB or IV (alternative scenario). Approximately 60% to 70% of NSCLC cases are first diagnosed at Stage IIIB or IV (Mazzoni et al. 2011; Molina et al. 2008), with the remaining 30% to 40% diagnosed at earlier stages which would make them ineligible for erlotinib treatment. If the DNA analysis was inconclusive a repeat test may be necessary. At the Peter MacCallum Cancer Centre the rate of re-testing is estimated at 10% of EGFR tests however this rate may be reduced if testing is limited to bronchoscopy and core biopsy samples. In pre-clinical studies reported by Roche

Diagnostics the cobas® EGFR assay exhibited an invalid rate of 3.0% compared to 23.8% by the Sanger method when utilising FFPET as the specimen of choice (Roche Diagnostics Internal data). FNA and pleural effusion samples give a lower cellular yield and the highest re- test rates. Where possible, the repeat test should be carried out using the original biopsy sample, however in some cases further biopsy may be required.
Apart from the situation of inconclusive EGFR gene mutation test results, there are other circumstances in which more than one biopsy or EGFR gene mutation test may be required. Where there are multiple tumours present, more than one biopsy and EGFR gene mutation test may be required to guide treatment, although in practice, it may be decided to sample only the most accessible tumour. Further mutations can occur in the development of the disease, changing EGFR gene mutation status from negative to positive, and inducing resistance to chemotherapy (Sequist et al. 2011). The decision to order further EGFR gene mutation testing under these circumstances is at the oncologist or treating specialist’s discretion. However these circumstances would be considered unusual and it is expected that on average there would be one test requested per patient.
EGFR activating mutations occur with greatest frequency in adenocarcinoma NSCLC patients, however they are also known to occur in large-cell NSCLC (Rosell et al. 2009). By restricting EGFR gene mutation testing to those with a diagnosis of non-squamous cell and NOS NSCLC the testing regime will include patient populations most likely to be affected by the mutation (adenocarcinoma and large-cell carcinoma). EGFR gene mutations have been reported to be found in only 0-1.1% of squamous cell NSCLC (Shukuya et al. 2011). NSCLC that has not been categorised by histological diagnosis (i.e. not otherwise specified or NOS) should also be included in the testing regime so as to avoid missing patients who may benefit from first-line erlotinib treatment. Further pre-selection of patients (the frequency of activation mutations is higher in females, Asians and non-smokers) is a consideration however a significant

_{proportion of M+ cases fall outside these demographics.}